Summary/Abstract Electrical stimulation of neural tissue, such as deep brain stimulation (DBS) and cortical stimulation, is widely applied therapeutic neuromodulation techniques for neurologic disorders. Penetrating electrodes (e.g., microwires and silicon probes) for DBS provide high spatial resolution, but are invasive, displacing neural tissue, producing acute insertion trauma, and potentially eliciting a foreign-body response. Surface electrodes, while less invasive, cannot generate a highly-localized electrical field. Motivated by these limitations, the goal of this proposal is to develop minimally-invasive and yet highly-localized neuronal stimulation using ultrasound. Focused acoustic beams with high energy are traditionally used for cellular ablation. Here, we propose to use low acoustic energy to avoid any ablation or lesion, exploiting the unprecedented features of Self-Focusing Acoustic Transducers (SFATs) that can focus 2 - 20 MHz sound waves at a sub-mm-sized area with electrically tunable focal length and force direction. We will conduct intracellular and extracellular experiments to determine the value and underlying mechanisms of neuromodulation effects induced by SFAT-based ultrasonic stimulation. The aims of this project are (1) to determine the optimal SFAT designs and fabricate SFATs with novel properties for the proposed intracellular and extracellular experiments and (2) to characterize the neuromodulatory function evoked by SFAT-based ultrasound stimulation in normal brain slices and test its neuromodulatory effect in epileptic brain slices. Using patch clamp and extracellular recording methods, we will monitor ionic flux and local field potentials, respectively, while varying the acoustic stimulation frequency, intensity, pulse width, pulse shape and pulse repetition frequency as well as the focal spot(s), focal size and force direction. The safety of acoustic stimulation will be assessed by histology. This project will provide insights into biologic mechanisms of ultrasonic neural stimulation, and if successful, could be a critical step toward the development of a minimally invasive alternative to neuromodulation by electrical stimulation in the treatment of neurologic disorders such as epilepsy.